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Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.

Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration.

Purpose: The number of persons who have successfully completed treatment for a cancer diagnosed during childhood and who have entered adulthood is increasing over time, and former patients will become aging citizens. Methods: Ten years ago, an expert panel met in Erice, Italy, to produce a set of principles concerning the cure and care of survivors of childhood and adolescent cancer. The result was the Erice Statement (Haupt et al. Eur J Cancer 43(12):1778–80, 2007) that was translated into nine languages. Ten years on, it was timely to review, and possibly revise, the Erice Statement in view of the changes in paediatric oncology and the number and results of international follow-up studies conducted during the intervening years. Results: The long-term goal of the cure and care of a child with cancer is that he/she becomes a resilient and autonomous adult with optimal health-related quality of life, accepted in society at the same level as his/her age peers. “Cure” refers to cure from the original cancer, regardless of any potential for, or presence of, remaining disabilities or side effects of treatment. The care of a child with cancer should include complete and honest information for parents and the child. Conclusions and implication for cancer survivors: Some members of the previous expert panel, as well as new invited experts, met again in Erice to review the Erice Statement, producing a revised version including update and integration of each of the ten points. In addition, a declaration has been prepared, by the Childhood Cancer International Survivors Network in Dublin on October 2016 (see Annex 1).

Introduction: Irradiation of brain tumors (BT) in children can lead to the loss of pituitary function, predominantly manifesting as deficiencies in GH and ACTH. Objective: To assess the incidence and nature of pituitary deficiency in relation to initial tumor location in children after radiotherapy of BT. Methods: Twenty survivors (16 males and 4 females) of radiation-treated BT aged 1.4–10.9 (median 3.6) yr at diagnosis were studied, 10 with supratentorial and 10 with infratentorial BT. Radiation doses to the hypothalamus-pituitary (HP) area ranged from 30 to 54 (median 45) Gray. Follow-up was 9.4–16.9 (median 12.2) yr. Basal pituitary hormone levels were measured every 6 months. When growth failure became evident or pituitary deficiency was suspected, provocation tests of the HP axis were performed to assess GH, ACTH, and TSH function. Results: GH deficiency (GHD) developed in 17/20 (85%) children. In 10 patients, it occurred 4 yr after radiotherapy and in 2, 11 and 12 yr after radiotherapy. Six (30%) patients developed secondary hypothyroidism and 4 (20%) developed ACTH deficiency. Precocious puberty occurred in 2 girls. The course of development and the severity of hormone deficiencies were similar for supratentorial and infratentorial tumors. Conclusion: The major hormonal effect of BT irradiation in children is GHD, which may sometimes take more than 10 yr to manifest. We confirm findings by others that ACTH insufficiency occurs less frequently in children than reported for adults. Tumor location has no prognostic significance regarding the loss of HP function.

Summary Objective The role of chemotherapy in thyroid sequelae after cancer treatment has not been studied systematically, especially in sarcoma patients. The aim of this study was to determine the incidence of post-therapeutic thyroid disorders and their contributing factors in a cohort of paediatric sarcoma patients. Design Late effects of sarcoma treatment have been collected prospectively within the Late Effects Surveillance System (LESS) in Germany, Austria and Switzerland since 1998. Patients We studied 340 relapse-free paediatric patients (median age at diagnosis 12·2 [interquartile range (IQR) = 7·3–15·6 years] treated for osteosarcoma, soft tissue sarcoma or Ewing's sarcoma within the COSS-96, CWS-96/CWS-2002P or EICESS-92/EURO-E.W.I.N.G.-99 therapy trials. In addition to polychemotherapy, 127 patients were irradiated (mean cumulative dose 47 ± 9·7 Gy), including 51 patients with irradiation to the head/neck region. Median follow-up was 24·6 (IQR = 11·9–44·9) months. Measurements We reviewed the results of yearly examinations of serum TSH and fT4 levels and thyroid ultrasound examinations. Results The incidence of thyroid disorders was 37% (19/51, 95% CI 24–52%) in patients with head/neck irradiation, and 11% (32/289, 95% CI 8–15%) in patients without irradiation to the head/neck. Thyroid disorders were more frequent in patients treated with idarubicin (P = 0·027) and trofosfamide (P = 0·016). We also found a significant association between raised TSH levels and treatment with trofosfamide (P = 0·008) or idarubicin (P = 0·037) (n = 250). Conclusions The incidence of thyroid disorders in the head/neck-irradiated group was high. Even without head/neck irradiation, we found an increased proportion of patients with thyroid disorders, possibly as a result of chemotherapy.

Late effects after radiotherapy in childhood and adolescence have mainly been characterized retrospectively with small patient numbers. Therefore the German Group of Pediatric Radiation Oncology (APRO) established the "RegIster for the evaluation of late Side effects after radiation in childhood and adolescence" (RiSK). After a pilot phase starting in 2001 documentation has been performed all over Germany since 2004. This analysis shows the first results of "RiSK".Radiation parameters including detailed organ doses as well as toxicity evaluations were collected prospectively from centers all over Germany in the study center. Standardized documentation forms were used. Documentation is planned for all children who receive radiotherapy in one of the German pediatric therapy trials.Until December 31st 2006, 696 documentations of radiotherapy and 526 acute as well as 836 late follow-up documentation forms have been collected. Altogether, 41 patients with late grade 3 and 16 patients with late grade 4-side effects were identified. Side effects mainly concerned joints with functional impairment (after combined radiotherapy and surgery), the bowel, skin and subcutis as well as blood parameters under continued chemotherapy. Patients with late side effects of a higher grade were mainly treated for Ewing's or soft tissue sarcomas (n=235 patients), representing 33.8% of all patients in this study.Fortunately, up to now only a few late grade 3 or 4 side effects of radiotherapy are shown for almost 700 documented patients. For further results, especially for the characterization of dose-effect-relationships, this study has to be continued with a higher patient number and a longer follow-up.

The aim of this study was to analyze cisplatin-induced ototoxicity in a recent study trial. Seventy-four patients who had received cisplatin for the treatment of osteosarcoma (median cumulative dose: 360 mg/m2) were investigated prospectively for ototoxicity in a multicenter trial. Hearing function was tested by audiometry. We evaluated the incidence and dependencies of hearing loss. After cessation of therapy, 51% of the patients showed a hearing loss of >20 dB in the frequency range of 4-8 kHz. Only in one patient a hearing loss was found at 2 kHz, and in none at 1 kHz. At a cumulative cisplatin dose of < or = 240 mg/m2, almost no ototoxicity was found. Incidence and magnitude of hearing loss increased significantly with a higher cumulative dose. Furthermore, hearing thresholds were significantly poorer in children

Therapy-related acute myeloid leukemia (t-AML) characterized by the t(9;11)(p22;q23) translocation is one of the most frequent secondary malignancies. The timing of the initiation of translocation and of development of the malignant t(9;11) clone during chemotherapy is presently unknown. In the present study, we backtracked bone marrow samples from three children during treatment for acute lymphoblastic leukemia (ALL). Two patients developed a t(9;11)-positive t-AML 19 and 30 months after therapy start, whereas the third patient, diagnosed with a rare t(9;11)-positive ALL, suffered from an ALL relapse 23 months after initial diagnosis. The genomic MLL-MLLT3 (MLL-AF9) fusion site was amplified by a multiplex, nested long-range PCR and used as a clonal marker for quantification of the MLL-MLLT3-positive cells during chemotherapy. The t(9;11)-positive clone was detectable 13 and 18 months after therapy start in both t-AML cases, which was 6-12 months before clinical diagnosis of the secondary malignancy. In the t(9;11)-positive ALL patient, the identical leukemic clone reoccurred during maintenance therapy after a short molecular remission, 8 months before clinically overt ALL relapse. The time course and characteristics of the genomic breakpoints in the present t-AML cases support the hypothesis of translocation formation as a result of defective breakage repair after topoisomerase II cleavage.

Children with metastatic retinoblastoma are considered to have a poor prognosis after conventional chemotherapy. We used high-dose chemotherapy (HDC) with peripheral hematopoietic stem cell transplantation in such patients in an attempt to improve their survival. Four patients with bone marrow metastases and one child with extraorbital disease were treated with HDC after achieving complete remission by enucleation and conventional chemotherapy. The child with extraorbital tumor was the only one to receive local irradiation. The conditioning regimen included thiotepa (900 mg/m(2)), etoposide (40 mg/kg) and carboplatin (1.5 g/m(2)) in four patients, and BCNU (300 mg/m(2)), cyclophosphamide (6.8 g/m(2)) and etoposide (1.6 g/m(2)) in one child. Hematologic recovery occurred without delay in all patients. The main toxicities were diarrhea, mucositis and infectious complications. No toxic deaths or any major late toxicities were observed. The child treated with the BCNU regimen developed a meningeal relapse 10 months after HDC, which was partially resected and treated with conventional chemotherapy, but not with radiotherapy. He is in complete remission (CR) 105 months off treatment. The other patients are in CCR for 107, 57, 9 and 8 months after HDC. HDC with thiotepa, etoposide and carboplatin may represent a curative option for children with extrabulbar or disseminated retinoblastoma responsive to chemotherapy. It may control occult CNS disease. The necessity to irradiate these children and the curative potential of this strategy for patients with bulky CNS disease remain to be determined.

To study cardiac function and the incidence of anthracycline-induced cardiotoxicity in children following treatment according to the nephroblastoma studies SIOP No.9/GPOH and SIOP 93-01/GPOH.Analysis of clinical status, echocardiography, and ECG findings prior to administration of anthracyclines (median cumulative doxorubicin dose: 250 mg/m(2) [range: 90-411 mg/m(2)] and after a median posttherapeutic interval of 2.9 years [range: 0-10.2 years]. Data on cardiac function before and/or after therapy could be obtained of 186 patients.Posttherapy left ventricular fractional shortening was reduced in 4/157 (2.5%) patients. Out of the 4 children, 2 had clinically reduced tolerance to exercise and received anticongestive therapy. Abnormal ECG findings that were not detectable prior to therapy were found in 7/124 (5.6%) children.The incidence of abnormal findings is low in our study group in comparison to data from the literature and might be due to the comparably short posttherapeutic interval.

The variety of endocrine late-effects after brain tumour therapy in childhood is well known. Growth is usually impaired first due to a hypothalamo-pituitary growth hormone (GH) deficiency or a radiation-induced neurosecretory dysfunction of GH secretion. Generally, all hypothalamo-pituitary axes can be affected. Disturbances of puberty, gonadal function, thyroid function and adrenal function can manifest after a long posttherapeutic interval. A retrospective analysis of the auxological and endocrinological data assessed within the German brain tumour study HIT 91 showed that endocrinological follow-up of these patients was not satisfactory. Therefore we have developed a concept for the new brain tumour study: auxological and laboratory parameters will be assessed before oncological therapy and in regular intervals (4, 12, 18, 24 months after the end of tumour therapy). 24 months after the end of tumour therapy all hypothalamo-pituitary axes are to be evaluated with pharmacological stimulation tests.

Lymphoma and leukemia are the commonest malignant diseases in patients with chromosomal breakage syndromes and immunodeficiency (Ataxia teleangiectasia (AT) and Nijmegen breakage syndrome (NBS)). With improved management of infections, malignant disease is more frequently diagnosed and has become one of the commonest causes of death in pediatric AT and NBS.In three consecutive multicenter therapy trials for pediatric non-Hodgkin's lymphoma (NHL) (NHL-BFM), 1569 patients with newly diagnosed NHL have been registered between 1986 and 1997. Nine patients with AT (n = 5) and NBS (n = 4) were identified and analysed.Median age of patients with AT and NBS at diagnosis of NHL was nine years. NHL-entities differed from non-AT/NBS-patients: diffuse large B-cell lymphomas, n = 7 (78%); ALCL, n = 1; lymphoblastic T-cell lymphoma, n = 1. Cervical nodes, paranasal sinuses and epipharynx were the sites most frequently involved. Stages were: I and II in three patients, III in five and IV in one patient. All patients received polychemotherapy according to tumor-entity and stage, none received radiation. Dose reductions according to individual tolerance concerned mainly ethotrexate, alkylating agents and epipodophyllotoxines. One patient died of toxic complications, two patients relapsed and died, one patient suffered from second malignancy. Five of nine patients are in 1. CCR after a median follow-up of five years.Patients with AT and NBS suffer from rare entities of pediatric NHL. Curative treatment is possible and should be attempted. Intensity of therapy should be adjusted to individual risk factors and tolerance. Alkylating agents, epipodophyllotoxines should be omitted, dose of MTX should be limited to 1 g/m2. Further cooperative trials using standardized approaches are required.

Nonresponders (NR) are patients (pts.) with no or insufficient response to initial treatment, which may be caused by either initial risk factors or poor therapy realization. In study AML-BFM 87, 49 NR of 307 patients (16%) did not achieve remission until the end of intensive chemotherapy and were analysed to assess the specific contribution of prognostic factors, therapy realization and complications of therapy. THERAPY AND METHODS: Therapy started with an 8-day induction therapy followed by a 6-week consolidation and two 5-day intensification blocks with high-dose cytosine-arabinoside and VP-16. Maintenance therapy was given for a total duration of 1.5 years. To evaluate the impact of treatment intensity in NR, we compared the dose compliance (DC = dose given/intended dose), the dose intensity (DI = dose per time given), the treatment results, and toxicity of the individual therapy phases in responders (CR) and NR.In 19 of 49 NR therapy was stopped before starting intensification blocks. Twenty-six NR received at least one block of intensification, and seven patients between three and six intensification blocks. Six children entered maintenance therapy. Twelve patients received a bone marrow transplant (9 allogeneic, 3 autologous). Six (5 after bone marrow transplantation) of 49 NR are still alive for 64 to 108 months. In nearly all patients induction therapy could be applied according to protocol (mean DC: 98%, range 85%-100%), whereas therapy realization was more difficult in the 2nd phase of therapy (mean DC: 92%, range 12%-113%). Deviations from the protocol in the treatment blocks (changes of dose and/or schedule) were mainly attributable to persistence of blasts (n = 33) and septic complications (n = 24). The mean relative DI of 1.01 was according to protocol. Bleeding and infectious complications in the individual therapy phases varied from 7% to 61%. NR compared to CR patients suffered significantly more often from bleeding during the first and second part of consolidation and from infections during the second part of consolidation. Withdrawal from protocol in NR was mainly due to persistence of blasts (n = 16), followed by bone marrow transplantation or other therapies (n = 13), and sepsis (n = 11).It is difficult to discriminate between nonresponse associated with blast persistence followed by complications and subsequent discontinuation of therapy and nonresponse due to insufficient therapy in patients with complications. Our analyses revealed that therapy with 2 intensifications according to protocol was feasible in 13 NR. Patients' condition permitting, therapy should not be stopped prematurely, in order to sustain the option of BMT after blast cell reduction.

Advances in the therapy of malignant brain tumors in children have led to a significant improvement in survival rates over the last few decades. As a result, the recognition and treatment of late effects have become more important. In addition to secondary tumors and deficiencies in cognitive and intellectual skills, the resulting endocrine disturbances play an important role.Own data and literature review.Deviations from the normal growth hormone secretion are usually recognized first and are most common, and have already been observed after conventional whole brain irradiation with 18 Gy. With some delay, other hypothalamo-pituitary deficiencies may occur, including panhypopituitarism. Puberty may come too early or too late or may not appear at all. Girls in particular, frequently experience an early and rapid pubertal development after brain tumor therapy, which may lead to further reduction in height due to an accelerated bone maturation. Functional disturbances of the thyroid and adrenal glands due to hypothalamic or pituitary deficiency are less common, and usually seen only after a radiation dose of over 40 Gy.Survivors of childhood brain tumors must be considered as long-term survivors, in whom the first therapy-induced long-term side effects appear almost immediately after the end of therapy. Maximum quality of life for the individual patient can only be achieved by long-term care and close cooperation of specialists in the different medical disciplines involved.

Background: Craniospinal radiotherapy for malignant brain tumors can result in a variety of neuroendocrine disturbances, among which are the development of growth hormone deficiency and early puberty, which can markedly reduce adult height. Methods: The authors report the case of a girl who received craniospinal radiotherapy for a medulloblastoma at the age of 3.4 years. At 9.1 years, growth hormone therapy was started, and spontaneous onset of puberty (Tanner stage B2) occurred at age 10.3 years. Interval until menarche was short, at only 0.9 years. Results: Although chronologic age at appearance of Tanner stages was within the normal range, the patient showed a rapid acceleration in skeletal maturation, resulting in adult short stature. Conclusion: Bone age seems to be a more precise parameter for biologic maturation in some patients after craniospinal irradiation than is clinical assessment of pubertal stages. Thus, if progression of bone age and decreasing final height predictions are noted, puberty should be stopped with gonadotropin-releasing hormone analogs, even if pubertal development seems to be adequate for chronologic age, because this increases the remaining time for growth hormone treatment.

Study objective was to evaluate retrospectively central nervous system (CNS) morbidity of children with acute lymphoblastic leukemia treated with intensive chemotherapy and cranial radiotherapy for a first isolated or combined CNS relapse. Neurological (Touwen), neuropsychological (CFT 20, Wechsler scales, d2 attention test) and neuromorphological (CT, MRI) assessments were performed in 17 children (9 girls, 8 boys) aged between 7 and 14 years. Patients were off therapy for median 4 years; cranial radiotherapy for CNS relapse (12-24 Gy) was given to all patients 2 to 9 years ago (median 5.5 years). Ten patients had received preventive cranial radiotherapy during front-line treatment, previously. In this group, the cumulative radiation dose ranged between 30 and 39 Gy. Patients received 12 to 30 intrathecal methotrexate doses (median 22). Compared with normative levels for age (100 points) performance IQ (89.9) and full scale IQ (92.0), Culture Fair IQ (88.3) and attention and concentration (90.9) were significantly impaired. Verbal IQ (95.5) was not significantly different from normal expectations. Neurological investigations of 16 patients showed mild signs in 7 (44%) of them, mostly of fine-motor skills and coordination, but no major motor disability. In MRI and CT, white matter changes or ventricular enlargement were noted in 10 of 16 patients (63%). Parent-completed questionnaires indicated problem behaviors in 5 children. Cumulative doses of methotrexate correlated significantly with neuropsychological test results. Children irradiated twice as well as girls had poorer cognitive functions, not being statistically significant. Despite pathological test results, all children attended a normal school and did not exhibit obvious impairment in daily life. In conclusion, CNS relapse and attendant therapy, mostly consisting of a second course of cranial radiotherapy, caused measurable intellectual deficits and CNS morbidity, which did not result in severely impaired performance. Periodic psychological und clinical examinations are recommended for recognition of delayed morbiditiy and early intervention.

Monitoring of therapy-related late effects after acute lymphoblastic leukemia (ALL) therapy in childhood has become an increasingly important area in posttherapeutic patient surveillance. The usefulness of conventional electro-encephalographic (EEG) investigations as part of these attempts is controversially discussed. However, EEG recordings have become a popular approach for judgement on the functional integrity of the central nervous system in this subject group. The present report focuses on this problem and discusses the question whether and to what extent conventional EEG recordings were correlated with further measures of central nervous system (CNS) integrity and therapeutic differences. EEGs were recorded in 110 subjects, asymptomatic long-term survivors of ALL in childhood, during a large retrospective multicenter study evaluating CNS late sequelae following antileukemic therapy in Germany and Austria. EEG findings were correlated with demographic data, illness- and treatment-related parameters, as well as with data on the morphological, neurological and psychological status of the participating subjects. At the time of follow-up the EEG was abnormal in 47 cases (42.7%). The most frequent EEG abnormalities observed were disturbances of the background activity (n = 45, 95.8%), followed by hypersynchrone activities (n = 1.0, 21.3%) and interhemispheric differences/focal slowing (n = 6, 12.8%). With exception of age at diagnosis, none of the observed EEG abnormalities showed a correlation with any of the aforementioned illness- or treatment-related parameters. Eighty percent of the observed EEG abnormalities were found in children younger than 5 years at diagnosis. Children less than 2 years of age as well as those above 5 years at onset of disease showed a significantly reduced prevalence of EEG disturbances compared to subjects between 2 and 5 years at diagnosis. Neither the degree of illness nor therapy-specific differences showed any relationship to EEG outcome. There was no specific EEG finding for a specific morphological substrate, neurological or psychological deficiency and vice versa. Overall, there was no beneficial effect of routine EEG testing in children following therapy for ALL. According to our data, the evaluation of conventional EEG recordings of otherwise asymptomatic ALL long-term survivors is not a very helpful measure for predicting the degree of behavioral deficiencies, neurological disturbances, or morphological CNS abnormalities, which may be present or will develop in this special subject group.

The effect of cranial irradiation on possible therapy-induced morphological central nervous system (CNS) side effects of children cured from acute lymphoblastic leukemia (ALL) is controversially discussed. In a retrospective multicenter study, 118 former ALL patients in first continuous remission were investigated using cranial computerised tomography (CCT) or magnetic resonance imaging (MRI) scans to evaluate CNS related impairments. Corresponding to the different kinds of CNS prophylaxis, the patient sample was divided: group A (n = 39) receiving intrathecal methotrexate (ITMTX) and systemical medium-high-dose methotrexate (SMHDMTX), group B (n = 41) cranial irradiated (in mean 16.8 Gy) and administering ITMTX and SMHDMTX, group C (n = 38) irradiated (in mean 17.1 Gy) and getting ITMTX. Pathologic scans showed atrophy, leukoencephalopathy, calcifications or grey matter changes. These findings were compared with the neuropsychological test results. Abnormal MRI or CCI scans were found in 61/118 patients (51.7%). Fifteen belonged to group A (38.5%), 23 to B (56.1%) and 23 to C (60.5%). Patients with definite CNS changes show reduced neuropsychological test results. The prevalence of brain alterations seems to appear twice increased after lengthening the posttherapeutic interval in irradiated patients as in nonirradiated patients. Irradiated patients as an age younger than 2 years at diagnosis may show a lower prevalence for developing CNS alterations. CNS alterations are not sex-related. Children treated with cranial irradiation in combination with SMHDMTX and/or ITMTX were at greater risk of developing morphological brain alterations than patients with chemotherapy alone. These alterations are partly correlated with reduced neuropsychological performances and seem to stay with a longer posttherapeutic interval.

Visual-evoked potentials (VEPs) were studied in 92 asymptomatic long-term survivors of acute lymphoblastic leukemia (ALL) in first complete remission 6-7 years after cessation of therapy in order to detect therapy-related disturbances in conduction velocity capacities within central nerve fibers. Subjects were grouped with respect to CNS prophylaxis: a) ith. MTX and 18 GY cranial irradiation (group A, n = 58), b) ith. MTX and iv. MHD-MTX, no cranial irradiation (group B, n = 34). At follow-up VEPs were abnormal in 10 subjects (10.9%) with comparable rates in both CNS prophylaxis groups (A: 7/58 [12.1%], B: 3/34 [8.8%]; p = 0.56). Participants with radiological signs of leukodystrophy (n = 14), all within the irradiated CNS prophylaxis group showed significantly prolonged P100 latencies and had a 6.1-fold increased relative risk to develop VEP disturbances. No correlation could be established between VEP outcome and illness- or treatment-related parameters. VEP outcome was not correlated with age at diagnosis or gender. Thus, VEP recordings showed a close relationship with radiation-induced CNS white-matter disturbances. However, their value for clinical practice, routinely performed follow-up evaluations or standardized posttreatment surveillance studies is negligible.

In 1987, a pilot trial (HIT 88/89) was initiated by GPOH to investigate the effectivity and toxicity of intense preradiation chemotherapy. The aim of this study was to improve the treatment of children with malignant brain tumors, but provided no standardized recording of auxological and/or endocrinological parameters. In 1993 a sub-project, "Endocrinological late effects", was started during the ongoing study to examine the late effects of treatment, and a retrospective evaluation was performed in order to standardize parameters.We considered auxological and hormonal data from those patients (n = 133; 78 m, 55 f) who were alive at the time of the survey, and had completed tumor therapy.Analysis of the growth pattern of the children after the end of therapy indicate impaired growth. Group 1 (n = 77, CA10 yrs): Mean height SDS at tumor diagnosis was +0.32 (n = 77), and fell constantly after completion of therapy to -0.75 (n = 16) after 3-4.5 yrs. Group 2 (n = 56, CA10 yr): Height SDS-CA fell from +0.24 (n = 45) at the time of diagnosis to -0.62 (n = 14) after 3-4.5 yrs. Unfortunately, only body height and weight were recorded regularly, data on sitting height, pubertal stage and bone age were incomplete. Endocrine evaluation after end of therapy was insufficient.A standardization of endocrinological follow up is necessary as soon as possible, for an adequate description of the endocrinological late effects.

An increasing number of children suffering from cancer has been treated successfully during the last 25 years using therapy protocols of the Gesellschaft für Pädiatrische Onkologie und Hämatologie. The patients had to undergo an interdisciplinary treatment modality and a mostly intensive chemotherapy. Late effects could result from this approach for the now 20,000 survivors in the Federal Republik of Germany. The executive committee of the GPOH founded a working group for the detection of late effects stretching over all therapy studies. The first report of this group describes a spectrum of relevant late effects and proposes investigations for their detection.

Between 1975 and 1991, 40 patients with newly diagnosed medulloblastoma were treated at the authors' institutions. After aggressive surgical resection 39/40 (98%) received craniospinal radiation therapy with a local boost to the posterior fossa and other macroscopically involved areas. A group of 29 patients was treated with adjuvant chemotherapy. The five-year actuarial survival and event-free survival were 75% and 65%, respectively. Survival was significantly better for patients treated after 1981 as compared to those treated between 1975 and 1980 (p = .02). Younger age (two to four years) was associated with a better prognosis (p = .02). The extend of resection, Chang-stage, radiation dose to posterior fossa and the use of chemotherapy did not significantly impact on survival and relapse-free survival.

Between 1978 and 1991, 31 patients with primary (n = 28) and recurrent (n = 3) ependymoma received external radiation after initial surgery. There were 26 cases of intracranial and five cases of spinal ependymoma. Histological grading revealed low-grade in 23 and high-grade tumors in eight patients. Craniospinal irradiation was given to 13 of 28 patients, whole cranial radiation with boost to posterior fossa in three and local treatment to twelve patients. Six of 28 patients received chemotherapy. Dose to the primary, tumor localisation, grading and extend of surgery did not significantly impact on survival and relapse-free survival. Age was a marginally significant prognostic factor for survival. In patients with intracranial ependymoma (n = 24) survival and relapse-free survival at five years were 54% and 42%, respectively. Patterns of recurrence showed a local recurrence alone in eight, a CNS-relapse with local recurrence in four and local recurrence with distant metastases in one case. Spinal seeding occurred in two of 13 after craniospinal irradiation and two of twelve patients after local treatment. The main problem in the treatment of ependymoma remains local control, the use of spinal irradiation does not seem to improve treatment results.

160 patients with a median age of 38 years (range two months to 84 years) having silicone rubber central venous access catheters for long-term parenteral nutrition or chemotherapy were studied prospectively. Two different types of catheters were used, the Broviac-type "life-cath" and the Groshong -catheter. Intraoperative complications were not noticed. Parenteral therapy was performed in 124 patients (81%) without any complications. After a mean postoperative interval of 36 weeks there were 34 catheters removed because of end of therapy. 78 patients died with the catheter in place. 40 catheters had to be removed before end of therapy due to catheter-related complications. Occlusion of the lumen occurred in nine patients after an interval from three to 20 weeks. Explantation of catheters due to a suspected catheter-related sepsis was performed in 17 patients. Both types of catheter showed a high cumulative patency rate of 90% after a twelve months period. However, there were catheters that had to be removed before planned end of therapy. Thus, the cumulative rate of functioning catheters is lower (44% of all catheters).

Complete remission (CR) rates of 80% are achieved with the AML-BFM protocols but one third of patients relapse within the first three years. There are few reports of treatment of relapsed childhood AML, and these deal with the evaluation of new drugs for frontline therapy. We performed a retrospective analysis to investigate how patients previously treated with the AML-BFM-83 protocol were treated after relapse and how many long term remissions were achieved. 48 of 139 patients relapsed after having achieved complete remission with the AML-BFM-83 protocol which consists of continous infusion of ARA-C 100 mg/m2 day 1-2, ARA-C 200 mg/m2 day 3-8, Daunorubicin 60 mg/m2 day 3, 4, and 5, and VP-16 150 mg/m2 day 6, 7, and 8, and an 8 week consolidation therapy consisting of Prednisolone, Thioguanine, Vincristine, ADR, ARA-C, Cyclophosphamide, intrathecal ARA-C and cranial irradiation followed by maintenance therapy. Duration of first remission ranged from 1.5 months to 66.3 months. Excluding 5 children with either isolated or combined extramedullary relapses and another 4 patients for missing data, 39 children were evaluable. 20 children received no therapy or palliative therapy while 16 patients received chemotherapy and another 3 children were transplanted in relapse. Although 9 different intensive chemotherapy regimens were used for reinduction, a high number (12 of 16 = 75%) of second complete remissions was achieved. Several therapeutic options were used to maintain a second remission: regular maintenance therapy (7 patients), allogeneous bone marrow transplantation (BMT) (2 patients), autologous BMT (3 patients).(ABSTRACT TRUNCATED AT 250 WORDS)

In a retrospective study from 1979 to 1989 17 tumors of the sympathic chain and the adrenal gland were analysed according to typical sonographic patterns. 13 tumors (10 neuroblastomas, 2 pheochromocytomas, 1 adenoma of the adrenal gland) were localized within the abdomen, 4 tumors (3 neuroblastomas, 1 ganglioneuroma) originated from the mediastinum. Neuroblastomas usually were great suprarenal masses with bad delineation and inhomogenous increased echogenicity in comparison with the liver. In more than 50% calcifications occurred, whereas cysts (15%) could rarely be found. The upper pole of the ipsilateral kidney usually was compressed and displaced caudally and laterally. The great intraabdominal vessels were usually displaced anteriorly and to the opposite side. The disturbed flow within the compressed intraabdominal vessels could reliably be shown by colour Doppler sonography as well as tumor vascularity. The 2 pheochromocytomas as well as the ganglioneuroma and the adenoma of the adrenal gland were round or oval, well delineated nodules with homogeneous liver like echogenicity. According to their typical sonographic patterns tumors of adrenal gland and sympathic chain can be differentiated from each other as well as from kidney tumors.

Recent epidemiologic findings for coronal and root surface caries, enamel fluorosis, and the periodontal diseases are reviewed. Incidences of coronal caries in children have continued to decline (at an accelerated rate in some populations) during the 1980s. Two possible reasons other than fluorides for these trends are a change in providers' criteria for treatment of pit and fissure caries and the use of dental sealants. Further declines are anticipated, particularly if benefits resulting from preventive programs can be extended to lower socioeconomic groups. The study of root caries has evolved to include concerns of standardized measurement, documentation of incidence in addition to prevalence, and use of multivariate analyses to identify potential explanatory variables. Evidence supports an increase in the prevalence of enamel fluorosis, generally of the milder forms; use of fluoride supplements and toothpastes at an early age may be risk factors for this condition. The prevalence of severe periodontal disease in the general population is low. Initial assessments of risks for periodontal disease progression have identified a number of potential factors that are related to the diseases in a complex way. Significant analytic advances have been made to aid in risk-factor identification.

Till now bone tumors are diagnosed radiologically. In this paper we describe the characteristic sonographic and colour Doppler sonographic features in 5 patients with histologically confirmed osteosarcoma. A large soft tissue tumor with echogenic osteosclerotic areas and echo-free caverns could be shown in all patients. Characteristic signs were destructions of the cortical layer and reactions of the periosteum. Compared to normal tissue an increased number of blood vessels with increased blood flow were visible by colour coded Doppler sonography in the region of the tumor. Sonography and colour coded Doppler sonography are important additions of conventional radiology to describe the structure, extension and blood supply of an osteosarcoma.

The aim of the study was to develop a method to obtain a single cell suspension from paraffin fixated neuroblastoma tissue for measuring the DNA content by flow cytometry, and to detect possible correlation between the histological grading and the DNA stemline, and to relate these findings to the patients' prognosis. 51 samples of the fixated neuroblastoma tissue were measured. It was possible to determine the DNA content in 38 probes of the material. 79% of the evaluated samples showed aneuploid DNA stemlines, 21% showed euploid stemlines. Despite the small number of probes it was found, that in relation to the histological grading of neuroblastoma a lower grade of malignancy correlated with an euploid DNA content and a higher grade of malignancy correlated with an aneuploid DNA content. A correlation between DNA stemlines and the patients' prognosis was not found.

Between 1979 and 1989 21 renal tumors (8 girls and 13 boys) were diagnosed and treated in the Pediatric Hospital of the University of Erlangen. Additionally, there was evidence of nephroblastomatosis in 5 children with Beckwith-Wiedemann Syndrome and hemihypertrophy. One of these infants developed a Wilms' tumor at the age of 3 1/2 years. The most frequent tumor was the Wilms' tumor, which was diagnosed in 14 children. Wilms' tumor are sonographically well delineated, round or oval tumors which often enclose small cysts (72%) but rarely calcifications (5%) and show inhomogenous liver like echogenicity. Metastasis in liver, spleen or abdomen occurred in 2 infants. The most frequent renal tumor in neonates was the mesoblastic nephroma (3 infants). All mesoblastic nephromas were well delineated round tumors with inhomogenous echo-texture and equal or increased echogenicity in comparison to the liver. They often enclosed small cysts but no metastasis or calcifications. Angiomyolipomas of the kidneys could be diagnosed in two children with tuberous sclerosis. These tumors were echogenic nodules spread all over the kidney. We found multilocular nephroblastomas with multiple irregularly delineated cysts in one child. In an other child multiple renal lymphomas simulating solid tumors with liver-like echogenicity could be found.

Long-term indwelling catheters of the Broviac, Hickman, Groshong type, and the Port Systems have proved highly suitable as a supportive measure in pediatric oncology. They are indicated for cytostasis, bone marrow transplantation and long-term parenteral nutrition. They provide reliable and safe venous access for therapy and blood sampling. Therapy is thus faciliated, and the quality of the patient's life is significantly improved by reducing the number of venipunctures required.

Bone marrow cells from eight children and young adults with acute nonlymphocytic leukemia (ANLL) were classified by morphological and cytochemical criteria. The expression of receptors for complement (C3) and IgG Fc, the binding of immunoglobulin to the surface of leukemic blasts, and the phagocytic ability were investigated and compared with the differentiation/maturation of cells of normal myeloid and monocytic lineages. Cells from two patients with monocytic leukemia exhibited IgG Fc receptors in high proportions. The stage of maturation or differentiation as evaluated by the expression of surface markers did not correlate morphologically with the determined state of maturation in the remaining cases. Simultaneous measurements of cellular RNA and DNA, using flow cytometry, were performed on five patients. An increase in RNA content of leukemic cells was detected in all patients and evidence of aneuploidy was observed in three patients. The cellular RNA content of ANLL was higher than that of ALL. This technique, therefore, appears to be useful as an additional tool for the discrimination of ALL from ANLL and for the rapid detection of aneuploidy.

In thirty-two patients with nephrotic syndrome (NS) phytohemagglutinin (PHA)-induced lymphocyte proliferation was studied at various stages of the disease. We demonstrated that lymphocyte transformation during acute exacerbation is markedly decreased, especially if cells are cultured in patient serum. During treatment with steroids PHA-stimulation improves. During full remission all patients showed their maximal lymphocyte stimulation. On the basis of these results and reports from the literature we postulate that patients with the NS have a T cell clone which inhibits the transformation capacity of the remaining lymphocytes through production of a heat stable serum factor. The same or a second factor produced by these lymphocytes could at the same time exert a toxic effect on the glomerular basement membrane.

The clinical course of Ph+CML and their terminal blastic stage is described in the following case histories. During blastic phase, cell surface markers, terminal deoxynucleotidyl transferase (TdT) activity, and flow cytometric measurements were used or determination of the blast cell phenotype which was undifferentiated by morphological and cytochemical criteria. A high proportion of blast cells expressed Fc receptors for IgG, TdT activity was normal in both children and RNA measurements of single cells flow cytometry showed a high RNA content in the majority of blasts. These findings are compatible with the phenotype seen in the myelomonocytic leukemias. Flow cytometry appears to be a useful adjunct to immunological methods and TdT activity for the rapid characterization of CML in blastic phase.

The different therapy modalities and course of disease of 42 patients with a malignant peripheral neuroepithelial tumor are retrospectively analyzed. Therapy was completed in 31 children, 25 of whom had a primary localized tumor and 6 a disseminated neuroepithelioma. 17 of the children with a localized illness survive disease free in contrast to no survivor in the group with a disseminated tumor. The effective chemotherapy combining vincristine, adriamycin, ifosfamide and actinomycin D must be complemented by an efficacious local control because malignant peripheral neuroepithelioma tend to recur locally. The prospective analysis of newly diagnosed patients and a standardized therapy regimen will show if malignant peripheral neuroepithelioma represents a distinct tumor entity, different from a Ewings-Sarcoma.

Cells belonging to the mononuclear phagocytic system may give rise to a wide variety of proliferative disorders. These neoplastic or reactive diseases of monocytes, histiocytes and macrophages are still poorly understood, both from a biological, clinical and pathological point of view. In 1984 a new type of non-Hodgkin's lymphomas has been described, which recently was termed large cell anaplastic lymphoma (LCAL). Since both "true" malignant histiocytosis (MH) and LCAL display some clinico-pathological similarities, we reevaluated eleven children with the primary diagnosis of MH, who entered the multicentric therapy study DAL-HX 83. On the basis of the typical morphology LCAL and not MH has been diagnosed in all cases. The Ki-1 (CD 30) positive tumor cells of LCAL can display different phenotypes, either T-lymphoid, B-lymphoid, histiocytic or neither of them (O-phenotype). Therefore we investigated the lineage specificity of tumor cells in 15 paediatric patients with LCAL. Tumor cells of histiocytic origin could be demonstrated in only one of them. In 7 patients the neoplastic cells were of T cell and in the remaining 7 cases of non T/non B cell (O) phenotypes, confirming the extreme rarity of MH in children. It is our opinion that MH and LCAL seem to be different diseases not only nosologically but also clinico-pathologically. In the multicentric therapy studies NHL-BFM 81 and NHL-BFM 83 the frequency of LCAL in childhood is compared to all other subentities at 3%.

Hexosaminidase isoenzymes P from serum of pregnant women and I2 from serum of leukemic children were compared using various biochemical methods, namely, ion exchange chromatography, isoelectric focusing, and molecular weight determination by gel filtration. Isoenzyme I2 is activated by calcium, magnesium, and manganese. The molecular weight of isoenzyme I2 was 110,000 compared to 130,000 of isoenzyme P. The widely differing molecular weights exclude the so far suggested identity of both enzymes. Both isoenzyme P and isoenzyme I2 possess beta-chains, however, they differ in chain structure and glycosylation. This different structure of isoenzyme P may be one of the reasons for its increase during pregnancy due to the resulting impaired clearance by liver sinusoidal cells.

Pain-management in pediatric-oncological patients is an interdisciplinary task. The working group pain--therapy of GPO tries to work up an analgesic concept for this group of patients. Pre-existing experience in the therapy with sustained release Morphine and Metamizol should be considered. The documentation-system is just worked up, we ask all pediatric oncological groups to cooperate.

The authors report on two patients with embryonic rhabdocytosarcoma of the orbit. The tumor in a nine-year-old girl was classified histologically as being of differentiated type and was characterized immunohistochemically by myoglobin. In a two-year-old girl an embryonic rhabdocytosarcoma of a less differentiated (intermediate) type was found which was characterized immunohistochemically by desmine. The differentiated tumor containing myoglobin, in the nine-year-old girl, responded better to chemotherapy. Eighteen months after institution of therapy both patients are healthy and free of recurrences. Immunocytochemical characterization of embryonic rhabdomysarcomas is clinically important, for both diagnosis and prognosis.

A 6 1/2 years old boy got completely blind within 3 days. Ophthalmoscopically regular findings suggested a retrobulbar opticus infiltration in a pediatric-diagnosed acute myeloic leukemia FAB-M2. A quick diagnosis and prompt cytostatic therapy combined with irradiation of the retrobulbar space opened the way for complete remission with bilateral optic atrophy. The ophthalmoscopic examination of 12 other leukemic children showed once more the involvement of the central nervous system with bilateral papilloedema, 2 times retinal hemorrhages and one vitreous bleeding; 8 children had no ocular symptoms. Comparing these findings to those described in literature, the authors point out the value of ophthalmoscopy to exclude ophthalmologic damages and to avoid side-effects of cytostatic therapy, fortunately not observed till now.

Four adolescents with polycythaemia are described where symptoms typical of the disease had already existed in childhood. Three patients fulfilled the criteria of a polycythaemia vera. In one female patient the possibility of familial erythrocytosis is discussed. Polycythaemia vera mononuclear cells formed erythroid colonies in cultures in the absence of erythropoietin. The patients were phlebotomized to maintain haematocrit readings of 40 to 45%. No case has yet progressed to myeloid metaplasia or acute leukaemia.

A variety of surface markers, terminal deoxynucleotidyl transferase (TdT) activity, morphologic appearance, and cytochemical composition were studied in a group of 16 patients (13 children, 3 adults) with acute lymphoblastic leukemia (ALL). In 9 children, no surface markers were detected on lymphoblasts (null-type ALL). Leukemic blasts of 4 children formed E-rosettes. These E-rosette-forming blasts from 3 adult patients with ALL, were studied for the presence of Fc receptors. Of the leukemic blasts from these 7 patients, 2--76% expressed receptors for IgG Fc. Only 3 of 7 patients showed 9--42% receptors for IgM Fc. In addition, complement receptors were investigated in 6 of those 7 patients with T-cell ALL. Complement receptors were detected on 9--70% of the E rosette forming blasts from all 6 patients. TdT activity was elevated in T-cell ALL and in children with null-type ALL. The heterogeneity of Fc receptor expression on leukemic blasts in these patients demonstrates a malignant proliferation of T cells in different stages of differentiation or maturation. This observation might be helpful in subclassifying T-cell leukemias with regard to prognosis and the response to therapy.

N-Acetyl-beta-D-Hexosaminidase (E.C. 3.2.1.30) activity was investigated in cell lines, urine and serum of leukemic children by various biochemical methods for its usefulness in classifying different types of leukemia. We demonstrated in our small series that the activity of the I-isoenzyme of hexosaminidase in serum was dependent on the amount of tumour burden at the beginning of induction therapy. However it was not specific for a certain type of leukemia. In contrast to other reports an increased hexosaminidase-I-activity was found not only in C-ALL-cell lines but also in a T-ALL. Furthermore our results exclude any diagnostic value of urine hexosaminidase for the classification of leukemias.

An aneuploid DNA stem line has been detected by flow cytometric measurements in 17 (29%) out of 59 children entered in the BFM 83 pilot study for ALL relapse. Of 17 DNA aneuploidies, 15 were hyperdiploid. Euploidy was observed in 28 of 34 patients with an early relapse, whereas 11 of 25 children suffering a late recurrence of disease showed aneuploid DNA stem lines. In contradistinction to ALL relapse, a significantly higher frequency (38%) of pretreatment DNA aneuploidy was measured in 376 newly diagnosed patients of the BFM trials. Our findings may reflect the impact of therapy on leukemic cell clones and their relapse pattern.